Method and device for the formation of biological cell material

ABSTRACT

A method for producing cell material ( 20 ) having multiple biological cells ( 21 ), which have a predefined geometrical arrangement, includes the steps of providing a manipulation tool ( 10 ) having a tool body ( 11 ), whose surface ( 12, 14 ) at least partially contacts the cell material ( 20 ), and adjusting the manipulation tool ( 10 ) using a change of geometrical properties of the surface ( 12, 14 ) in such a way that the geometrical arrangement of the cells ( 21 ) is changed. A manipulation tool for performing a method of this type is also described.

The present invention relates to methods for forming, particularly forshaping and/or depositing, cell material having multiple biologicalcells, particularly methods for setting or changing a surface topographyof a cell material and methods for geometrical structuring of cellmaterial, such as methods for tissue engineering. The present inventionalso relates to manipulation tools for performing these methods,particularly substrates for cell material, such as cell cultures ortissue, and shaping tools, using which the geometrical shape and/ordimensions of the cell material are changeable. The present inventionalso relates to novel applications of the cited methods and manipulationtools.

In medicine, biotechnology, and biochemistry, essential objects exist inthe examination or manipulation of biological cells, particularly inconnection with medicinal cell therapy and tissue engineering, in thatcell formations or cell groups are provided having a predefinedgeometrical arrangement of the individual cells. For example, the shapeof a cell material which is implanted into an organism is to be tailoredas well as possible to the geometrical conditions at the implantationlocation. Adapting the shape of the implant material by suitablemechanical trimming (cutting) from a cell culture is known frompractice. However, this is disadvantageous since damage to the cells orthe cell material may have undesired effects during the tissueregeneration after the implantation. In numerous experiments known frompractice, the desired regeneration or new growth of a cell or tissuetype did not occur, but rather, for example, an induction of tumors. Itis assumed that induction of tumors as uncontrolled cell reproduction ofcells, is encouraged by physical, chemical, or mechanical externalinfluences at the implant location. These influences may not beimplemented reproducibly or at least detected using the currenttechnologies.

A further example of the shaping of cell material is the examination ofactive ingredients (testing of pharmacological active ingredients) ontissue models. Preferably, spheroids are used as tissue models, whichmay be produced as spherical formations through layered growth of cellmaterial on an inner core made of cells. A disadvantage of conventionaltissue models is their restricted size. For example, until now onlyspheroids up to a diameter of approximately 150 μm have been able to beused. At larger diameters, problems arise in the nutrient supply of theinner cells. The vitality of the inner cells is restricted and dying ofthe cells from the inside to the outside may occur.

A further object in tissue engineering which has not been achieved up tothis point is the production of structured composite material from cellmaterials of different types of cells or from biological cells andsynthetic materials. A disadvantage is that up to now compositeformations have been associated with mechanical injuries of cells orcell material.

The objects cited in cell therapy and the results in tissue engineering,which have been partially unsatisfactory up to this point, currentlyrepresent the most important restrictions and delays of a broadapplication of these methods in biotechnology and medicine.

The object of the present invention is to provide improved methods forforming cell material having a predefined geometrical arrangement of theindividual cells, using which the disadvantages of conventional methodsare overcome and which are particularly capable of shaping and/orgenerating cell material without injuring individual cells. It is alsothe object of the present invention to provide improved manipulationtools for performing methods of this type, using which the disadvantagesof conventional cell or tissue technologies are overcome. It is afurther object of the present invention to specify novel applications ofthe shaping, cultivation, or generation of cell material.

These objects are achieved by methods and manipulation tools having thefeatures according to claims 1 or 20. Advantageous embodiments andapplications of the present invention result from the dependent claims.

In regard to the method, the present invention is based on the generaltechnical teaching of setting the geometric arrangement of cells in thecell material using a manipulation tool, which at least partiallycontacts a cell material to be manipulated, by changing the surfacegeometry of the manipulation tool in a predefined way. The surfacegeometry may be changed according to the present invention in regard toat least one of the features of area, orientation in relation to a fixedreference system, surface shape, and surface structure. The cells of thecell material which contact the tool surface advantageously follow thesurface movement, wherein the cells remain unchanged in their physicaland chemical state during the surface movement. The geometrical changeof the tool surface exclusively causes a rearrangement of the cells,particularly an injury-free displacement or shifting of cells, in whichcells in contact with the tool body or cells lying deeper in the cellmaterial are deformed or changed in their spatial position, but do notrelease any chemical signals in the form of messenger substances orsubstance secretions.

Cell material is generally understood here as an accumulation of cellswhich are connected to their environment via adhesion contacts(macromolecular chemical bonds, no van der Waals bonds) . The cellmaterial is, for example, a composite or aggregation of individualcells, a tissue (combination of identical differentiated cells), or anorgan. The non-liquid composite of individual cells may additionallycontain synthetic components, such as a synthetic matrix material. Theformation of cell material is generally understood here as a change ofthe shape, density, size, and/or structure of cell material.

The manipulation tool is generally a foreign body or object made of amaterial which may be delimited in relation to the cell material havinga fixed surface, whose geometrical properties are changeable at least inpartial regions. The manipulation tool may, for example, have asubstrate for cell culture, a probe in the cell material, or a stamp forshaping. The manipulation tool is adjustable in such a way thatgeometrical properties of its surface change in regard to at least oneof the above-mentioned features. The velocity of the adjustment isreferred to as the advance velocity.

The present invention is particularly based on the followingconsiderations of the inventors. It was first recognized that thereactions of cells in a tissue or a cell composite, for example, whichhave had different results up to now, are caused as cells in theexisting cell material are injured or destroyed by introducing a tooland wound effects are thus induced. In the event of a cell or tissueinjury, chemical signals (emission of molecular messenger substances) orcellularly supported processes, such as a fibroplast immigration, afibronectin excretion, or the like are generated. The reaction ofinjured cells influences the effect of the cells or additives. Forexample, stem cells behave differently in the environment of a cellinjury than stem cells in intact cell material. Secondly, the inventorshave found that, contrary to current expectations, even adhesivelybonded cells may be spatially displaced without injury. This allows themechanical insertion of tools into cell material. The cells remainuninjured during the movement of the tool surface in and/or through thecell material if the advance velocity is sufficiently low that adhesioncontacts between the cells detach in natural ways, i.e., ways which donot influence or destroy the cells, and may be reformed in the changingenvironment.

The above-mentioned requirements may be completely fulfilled by thegeometrical adjustment of the tool surface and the injury-free.displacement or shifting of cells associated therewith. Damage orimpairment of the cell material is excluded. The physical, chemical, andmechanical state of the cells may be completely characterized andmaintained. Damaging contacts between cells and surfaces of foreignbodies are avoided, cellular signals due to undesired surface contactsare suppressed. The cell manipulation is performed extremely carefullyby the injury-free movement. The manipulation tool may be guidedaccurately into a specific configuration in the cell material.

According to a preferred embodiment of the present invention, themanipulation tool is adjusted at a advance velocity which is less thanor equal to a reference velocity determined by the physiological bondingrate of biological cells (bonding velocity of the cells during theirnatural cell movement) . The natural cell movement (cell locomotion)includes the change in location of a complete cell on a fixed surface orin cell material by a rearrangement of adhesion contacts of cell organs(membrane organs, such as membrane protuberances), as are described, forexample, by M. Abercrombie et al. in the publication “The Locomotion OfFibroblasts In Culture” (“Experimental Cell Research”, Vol. 67, 1971,pages 359-367) and by L. P. Cramer in the publication “Organization andpolarity of actin filament networks in cells: implications for themechanism of myosin-based cell motility” (“Biochem. Soc. Symp.” Vol. 65,1999, pages 173-205).

The physiological reference velocity is known per se (see, for example,G. Fuhr et al. in “Biol. Chem.”, 1998, Vol. 379, pages 1161-1173) ormeasurable on animal or human cells. The bonding rate of interest may bederived by measuring the dynamics of adhesion patterns of individualcells on artificial surfaces, for example.

The advance velocity generally refers here to the velocity at which thesurface of the manipulation tool moves in relation to the cell material.This velocity may relate to the entire surface per se, specific shapingelements, which represent parts of the surface, or a surfaceenlargement. In the event of a surface expansion, the advance velocityrefers, for example, to the relative velocity of reference points duringan enlargement of the surface. Upon adjustment of the advance velocity,the manipulation tool may advantageously move or rearrange cells in anaturally occurring composite without injury. The advance velocity isadapted to the cell movement occurring permanently in the tissue. Forexample, it is known that specific types of immune cells (e.g.,macrophages), may move even through dense tissue by displacing existingcells. The inventors have found that surprisingly this displacementmovement may also be implemented using probes which are significantlylarger than immune cells and have macroscopic dimensions in thesubmillimeter to centimeter range, if the cited advance velocity is set.During the movement or production of the tool surface, macromolecularbonds running between the cells (for example, membrane-relatedmacromolecules of the integrin and cadherin families) are separated andrelinked to the probe surface, for example.

Special advantages of the present invention result if the advancevelocity of the manipulation tool is selected in a velocity range from0.1 μm/h to 1 mm/h, preferably in the range from 1 μm/h up to 500 μm/h.The bonding rates of the formation and breakdown of macromolecularbonds, which are typically mediated by membrane-related macromoleculesof the integrin and cadherin families, lie in this velocity range. Thepreferred velocity ranges correspond to the velocities of the cellmovement of fibroplasts, macrophages, lymphocytes, chondrocytes, ortumor cells in particular. Advantageously, if a advance velocity thislow is set, the position and shape of the tool surface may be set at ahigh precision of approximately +/−1 μm or even less. The propulsionvelocities in the cited ranges correspond to the active endogenicmovement velocities of cells in and on tissue. The movement of the probethus causes a permanent formation and restructuring of the cells in thedirect environment of the probe surface, displacement of the cells beingencouraged by the permanently acting advance force.

If the manipulation tool is subjected to a permanently acting advanceforce, its movement at the desired advance velocity may advantageouslybe performed even with the lowest application of force. This allows theuse of drive devices having low power. If the advance force is formed bya mechanical pressure force, advantages for the transmission of theadvance force to the probe may result. If the advance force is formed byforces in electrical or magnetic fields, advantages may result for theconstruction of an injection device, since the advance forces may beexerted via remote action.

Special advantages may result if the method according to the presentinvention is executed on cell material which is located outside ananimal or human organism. The cell material may be positioned undersuitable cultivation conditions on a fixed carrier, which applies thecounterforce to the exertion of the advance force. The cell material andthe probe may be positioned with higher precision.

Alternatively, the cell material may be located in the composite in aliving organism. The manipulation tool may, for example, be inserted asan examination probe, biopsy tool, or injection tool into tissue. Theinsertion occurs, because of the low advance velocity, in a state inwhich the affected tissue is held fixed in one location on a carrier,e.g., with the surrounding part of the organism. The use of ananesthetic is preferred for the immobilization, but is not absolutelynecessary in regard to the freedom of injury of the method, however.

According to a further preferred embodiment of the present invention,the adjustment of the manipulation tool may comprise an expansion of thetool surface. The cell material to be manipulated is positioned on thetool surface. The cell material forms a cell layer whose thickness isreduced by the expansion of the surface and/or in which gaps arise inwhich the tool surface is exposed. Advantageously, the production of anenlarging layer composite of the cell material is thus made possiblethrough growth of cells from an adjoining cultivation medium. Thisembodiment of the present invention may therefore particularly haveadvantages for providing the above-mentioned tissue model for activeingredient testing.

According to a first variant, the manipulation tool is at leastpartially made of an elastic material which forms the tool surface whichcontacts the cells and which is stretched during the manufacture of themanipulation tool. The elastic material (e.g., plastic, rubber)advantageously forms a closed, continuous surface. Alternatively,according to a second variant, the adjustable surface may be made of anonelastic material, such as lamellae made of metal or plastic which aredisplaceable into one another, advantages for the precision of thechange of the geometric surface properties able to result.

If, according to a further modification of the present invention, themanipulation tool has a hollow body which has an inner cavity with aninner surface which is enlarged during the adjustment of themanipulation tool, advantages may result for providing spheroidal tissuemodels. According to different variants of the present invention, thecell material may be positioned externally on the hollow tool body, onthe inner surface of the tool body, or on both inner and outer surfaces.These variations have advantages for providing layered tissue modelsmade of different types of cells, which may grow from the outside or theinside on the tool surface, the substrate area available beingcontinuously enlarged through the adjustment of the surface according tothe present invention. An undesired high layer thickness, which mayresult in insufficient supply of lower lying cells, may advantageouslybe avoided, significantly larger spheroids than in typical tissue modelssimultaneously being able to be produced.

The hollow manipulation tool is preferably made spherical with adiameter in the range from 0.01 mm to 10 cm.

If, according to a further variation of the method according to thepresent invention, the formation of the cell material comprises thegeometric rearrangement of the cells by adjusting the tool surface andsimultaneous growth of cells from a surrounding medium, advantages forthe generation of cell cultures having a predefinable maximum thicknessmay result. Accordingly, an independent object of the present inventionis a cell cultivation method in which cells from a cultivation mediumgrow on an enlarging substrate surface. Special advantages may resultfor tissue engineering if the cell material is produced in layers on orin the hollow tool body from different types of cells.

The tool surface may be enlarged by exerting a hydrostatic pressure onthe interior of the manipulation tool. For example, according to anadvantageous variation of the present invention, the hollow tool made ofan elastic material may be connected to a pressure line (such as aliquid line), through which a liquid or a gas may be introduced into theinterior of the tool under pressure. The stretching of the tool surfaceis performed by supplying liquid or gas. The stretching using a liquidhas the advantage that the supply liquid volume is directly associatedwith the enlargement of the surface. For the above-mentioned depositionof cell material on the interior of the hollow body, it may beadvantageous if a cell suspension, which conveys the cells to becultivated into the interior, is used as the liquid for stretching thetool surface.

For the application in tissue engineering, it may be advantageous if thesurface of the tool body is made of a material which allows anelectro-physiological contact, a substance transfer between the interiorof the tool and its environment, and/or cell contacts between theinterior and exterior.

According to a further, preferred embodiment of the present invention,the tool body contains at least one displaceable shaping element, theshaping element projecting out of the tool surface upon the adjustmentof the tool body and thus changing the surface design. The at least oneshaping element provides the tool body with the function of a plunger,whose plunger shape may be adapted variably to the particularrequirements by the displaceability of the shaping element. If multipleshaping elements are provided, the variability in the design of theplunger surface is advantageously elevated.

According to a variant of the present invention, the tool having the atleast one shaping element may be used as a cell culture carrier whichdetermines the shape of the cell culture. Alternatively, themanipulation tool having the surface whose shape is determined by theposition of the at least one shaping element may be pushed onto the cellmaterial like a plunger.

An independent object of the present invention is a biological cellmaterial or cell-carrier composite material produced using the methodaccording to the present invention, such as a cell spheroid which isformed by a cell material on an expanded carrier surface.

In regard to the device, the above-mentioned object is achieved byproviding a manipulation tool which comprises a tool body having atleast one surface, whose shape and/or size is adjustable, and a settingdevice for adjusting the surface. Advantageously, upon contact with acell material to be manipulated, this tool allows the cell material tobe embossed with the surface design. If the setting device for changingthe surface geometry is set up having a characteristic advance velocitycorresponding to a physiological reference velocity of biological cells,the above-mentioned advantages result for injury-free rearrangement ofthe cells during the shaping.

According to an especially advantageous variant, the surface of themanipulation tool is provided with a structure or coating whichencourages an adherent adhesion of biological cells. The bondingmaterial forms the tool body, at least the front of the tool body, or acoating on at least on the front of the tool body. It is made of, forexample, fibronectin or collagen. This embodiment of the presentinvention may have advantages in regard to elevation of the bondingspeed during the displacing movement of the probe through the cellmaterial. The bonding material may alternatively have characteristicstructure sizes in the sub-μm range, due to roughening, so that thebonding of the cell material to the probe is encouraged.

The surface of the manipulation tool may additionally be equipped with astructure or coating which blocks an adherent adhesion of biologicalcells at least in partial regions of the surface. For example, chemicalcompounds known per se, such as hydrophobic silanes and hydrophilicpolymers, are provided as the coating.

Further details and advantages of the present invention are described inthe following with reference to the attached drawings.

FIGS. 1 and 2 show illustrations of the production and rearrangement ofcell material according to a first embodiment of the present invention,

FIG. 3 shows an illustration of a radial expansion movement of amanipulation tool according to the present invention,

FIGS. 4 and 5 show an illustration of a tool surface having multipledisplaceable shaping elements, and

FIG. 6 shows a shape embossing of cell material according to the presentinvention using a manipulation tool.

FIGS. 1 and 2 illustrate the principle according to the presentinvention of generating hollow spheres or other hollow geometries fromcell material in a predefined way. For this purpose, a manipulation tool10 is provided having an elastic, hollow tool body 11 and a pressureline 13, via which an external pressure source 30 (only shown in partialimage A) is connected to the interior 31 of the tool body 11. Theschematically shown pressure source 30 forms an setting device foradjusting the surface 12 of the tool body 11. It comprises a liquidreservoir and a pump, for example.

The tool body 11 forms a balloon made of rubber, for example, which hasa diameter of 0.01 mm in the relaxed state, for example, and may havediameter of up to 100 mm in the stretched state, for example. Acapillary made of steel or glass, for example, is used as the pressureline 13. If the material of the tool 10 comprises partially-permeable,elastic plastic material (e.g., silicone membrane), the generation ofmaterial gradients in the cell tissue is advantageously made possible.

By injecting air or a liquid into the interior 31, the surface 12 of thetool body 11 may be enlarged, the shape being essentially maintained.The enlargement occurs in such a way that neighboring reference pointson the surface 12 move apart from one another at a velocitycorresponding to the above-mentioned physiological reference velocity.Correspondingly, cells on the surface 12 may follow the stretchingmovement without being subjected to undesired mechanical destruction.Partial images A and B of FIG. 1 show how a monolayer of cells 21 from asurrounding cell suspension 81 initially grows on the surface 12 of therelaxed tool body. By enlarging the surface 12, the space for enlargingthe cell monolayer 20 is continuous enlarged.

By adding further cell types 22, 23 to the external medium and/or theinternal medium, flexible tissue-type cell layers may be generated, as aschematically illustrated in partial image C.

FIG. 2 shows the cultivation of cell material 20 on the inner surface 14of the hollow body 11 in three different expansion states. The cavity 31is filled with a cell suspension from the liquid reservoir of thepressure source 30 via the pressure line 13. Adherent growing cells(e.g., fibroblasts, macrophages, or tumor cells) actively colonize theinner surface 14. For many types of cells, a contact inhibition occurswhen the substrate surface is completely covered. This means thatfurther reproduction is ended as soon as a monolayer has been formed.Through the stretching of the tool surface according to the presentinvention, this process may be controlled in a targeted way.

The interior 31 may be charged with different types of cellssequentially or simultaneously, as is shown in the largest stretchingvariation in FIG. 2, so that a cell material similar to tissue, having afunction corresponding to the types of cells participating in theformation of the cell material is generated. In this variation as well,the interior 31 may be in electro-physiological contact with theexternal medium 81.

FIG. 3 shows an example of a radial expansion movement of acapillary-shaped tool 10, whose body 11 is made of an elastic material(such as plastic, rubber) or a non-elastic expandable material (such aslamellae made of steel or plastic or the like which are displaceable inrelation to one another). By a pressure elevation in the hollow channel31 of the tool 10, its diameter may be expanded, injury-freedisplacement of the cells occurring. The diameter of the tool body 11enlarges at the advance velocity described above.

FIGS. 4 and 5 illustrate a manipulation tool 10 which has multipleshaping elements 15, each of which is individually displaceable using ansetting device 30, which is attached to a base part (not shown). Eachshaping element 15 has a cuboid shape having a top 16. The total numberof the tops 16 or at least a yielding, layered cover element 17positioned thereon (see FIG. 5) form the surface 12 of the manipulationtool 10, which is used for shaping cell material 20. The shapingelements 15 form the tool body. The tops 16 have typical dimensions inthe range from 0.01 mm to 5 mm. The shaping elements 15 are oriented sothat the tops 16 form a matrix arrangement made of linear rows andcolumns. The displacement of the shaping elements 15 in relation to thebase part is performed using positioning motors or piezoelectric drives,for example. The tool surface is structured depending on the selectedpropulsion of a shaping element 15. Individual shaping elements 15 maybe separable from the setting device 30 in order to form holes in thecell material, for example.

The cover element 17 has the advantages that the tool surface issmoothed locally and the removal of the cell material from the tool ismade easier. The cover element 17 comprises a film (such aspolyurethane) or a membrane, for example, which extends over all shapingelements 15 and on which the cells are positioned. Alternatively, one ormore cover elements 17 may be provided, which only extend over one ormore partial groups of shaping elements 15. Removable adhesion of thecover element 17 to some or all tops 16 of the shaping elements 15 maybe provided.

The cover element 17 may be made of a synthetic polymer material and/orof a material occurring naturally in biological organisms, such aschitin or bone matrix material, in one or more layers. The cover element17 may also carry a structured coating which encourages adherentadhesion of biological cells in partial regions and blocks it in otherregions.

For the production according to the present invention of cell material,the cell material is first positioned on the tool surface 12, i.e., onthe entirety of the tops 16 or the joint cover element 17. For thispurpose, for example, growth from a cultivation medium 81 in a culturevessel 82 (see FIG. 5) is provided. For reasons of clarity, onlyindividual cells 21 are shown in FIG. 4. The surface of the manipulationtool 10 is subsequently adjusted by advancing the shaping elements 15into the particular desired positions. This advance occurs at theabove-mentioned physiological reference velocity, so that during thedeformation of the cell material, injury-free displacement andrearrangement of the cells occurs. Subsequently, the cell material maybe detached from the manipulation tool 10.

FIG. 4 also illustrates that the individual tops 16 of the shapingelements 15 may be formed differently in order to additionally modifythe cell material at the particular positions. For example,microstructures (see at 16 a) may be provided for improving the adhesioncapability of the tops 16 or additional structure elements, such as thepyramid shape 16 b, may be provided to make a structure in the cellmaterial. Furthermore, individual or all shaping elements 15 may carryan adhesion-promoting coating 16 c.

A manipulation tool as shown in FIG. 4 may alternatively be used as animprinting tool, as is illustrated in the image sequence shown in FIG.6. In a starting situation as shown in partial image A, a cell material20 is located on a carrier 80, which is to be deformed in accordancewith the method according to the present invention. The manipulationtool 10 having multiple displaceable shaping elements 15 is positionedover the initially free surface of the cell material 20. Themanipulation tool 10 is moved toward the cell material 20 until the tops16, which point downward in this case, contact the cell material 20.Subsequently, as shown in partial image B, the surface 11 of themanipulation tool 10 is adjusted through the targeted propulsion ofindividual shaping elements 15. The advance movement is performed at theabove-mentioned physiological reference velocity of biological cells.The individual shaping elements 15 displace the cells in the cellmaterial without injury.

Subsequently, as shown in partial image C, the manipulation tool 10 isremoved. The surface shape of the tool remains in existence as acomplementary structure in the cell material 10. To make it easier toseparate the manipulation tool 10 from the cell material 20, the tops 16of the shaping elements 15 may be provided with a coating on whichadhesion of cells is suppressed. The coating is performed, for example,using the polymer Polyhema. Finally, the gaps introduced into the cellmaterial may be filled with other cells or a synthetic matrix material25 as shown in partial image D.

The shape and cells or additives 20 possibly supplied in the cellmaterial are selected depending on the concrete task in the scope of thetissue engineering. For example, using the sequence shown in FIG. 6,epithelial cells having a predefined structure may be connected totissue cells.

The features of the present invention disclosed in the abovedescription, the claims, and the drawing may be significant bothindividually or in combination for implementing the present invention inits various embodiments.

1. A method for producing cell material having multiple biologicalcells, which have a predefined geometrical arrangement, comprising thesteps of: providing a manipulation tool having a tool body, whosesurface at least partially contacts the cell material, and adjusting themanipulation tool using a change of geometrical properties of thesurface such that the geometrical arrangement of the cells is changed.2. The method according to claim 1, wherein the adjusting of themanipulation tool is performed at an advance velocity less than or equalto a physiological reference velocity of the cells.
 3. The methodaccording to claim 2, wherein the adjusting of the manipulation tool isperformed at an advance velocity in a range from 0.1 μm/h to 1 mm/h. 4.The method according to claim 1, wherein, during the adjusting of themanipulation tool, the surface of the manipulation tool is enlarged. 5.The method according to claim 4, wherein the manipulation tool has anelastic material that is stretched during the adjusting.
 6. The methodaccording to claim 4, wherein the manipulation tool has a non-elasticmaterial that is expanded during the adjusting.
 7. The method accordingto claim 4, wherein the manipulation tool has a hollow body having aninterior which is enlarged during the adjusting.
 8. The method accordingto claim 7, wherein the cell material is positioned externally on thehollow body and/or in the interior of the hollow body.
 9. The methodaccording to claim 8, wherein, during the adjustment of the surface,individual cells or cell groups adhere externally on the surface and/orin the hollow body.
 10. The method according to claim 7, wherein thecell material is positioned in layers made of different types of cellsexternally on and/or in the hollow body.
 11. The method according toclaim 7, wherein the interior has a pressure applied to it via apressure line to adjust the hollow body.
 12. The method according toclaim 11, wherein a cell suspension is introduced into the interior toadjust the hollow body.
 13. The method according to claim 7, wherein amass transfer occurs between the interior of the hollow body and anenvironment.
 14. The method according to claim 4, wherein the tool bodyincludes at least one shaping element, which is displaced during theadjusting of the manipulation tool, so that a shape of the surfacechanges.
 15. The method according to claim 14, wherein the tool bodycontains multiple shaping elements, which are displaced during theadjustment of the manipulation tool.
 16. The method according to claim1, wherein, during the adjusting of the manipulation tool, at least oneof the surface and the shaping elements is at least partially pushedinto the cell material and an imprint shape of the surface of themanipulation tool formed in the cell material.
 17. The method accordingto claim 16, wherein further cells or a synthetic matrix material are/ispositioned on the cell material.
 18. The method according to claim 1,wherein the cell material comprises a composite material made of thebiological cells or of the biological cells and a matrix material. 19.The method according to claim 1, wherein the geometrical arrangement ofthe cells is changed using the manipulation tool outside an animal orhuman.
 20. A manipulation tool for producing cell material havingmultiple biological cells, which have a predefined geometricalarrangement, comprising: a tool body having at least one surface and ansetting device for adjusting the tool body, so that geometricalproperties of the surface change.
 21. The manipulation tool according toclaim 20, wherein the setting device adapted to adjust the tool body atan advance velocity which is less than or equal to a physiologicalreference velocity of the cells.
 22. The manipulation tool according toclaim 21, wherein the setting device is adapted to adjust the tool bodyat an advance velocity in a range from 0.1 μm/h to 1 mm/h.
 23. Themanipulation tool according to claim 20, wherein the surface of the toolbody is adapted to be enlarged during the adjusting.
 24. Themanipulation tool according to claim 23, wherein the tool body has anelastic material.
 25. The manipulation tool according to claim 23,wherein the tool body has a non-elastic, expandable material.
 26. Themanipulation tool according to claim 23, wherein the tool body comprisesa hollow body having an interior which is enlarged during theadjustment.
 27. The manipulation tool according to claim 26, wherein thehollow body is connected to a pressure source via a pressure line. 28.The manipulation tool according to claim 23, wherein the tool bodycontains at least one displaceable shaping element.
 29. The manipulationtool according to claim 28, wherein the tool body contains multipledisplaceable shaping elements, which are positioned in linear rows andcolumns in a matrix.
 30. The manipulation tool according to claim 28,wherein at least one cover elemental which forms the surface, ispositioned on the shaping elements.
 31. The manipulation tool accordingto claim 20, wherein a structure or coating, which encourages adherentadhesion of biological cells, is provided on the surface.
 32. Themanipulation tool according to claim 20, wherein a structure or coatingwhich blocks adherent adhesion of biological cells is provided on thesurface.